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BMC Medicine
RESEARCH ARTICLE Open Access
Chronic cerebrospinal venous insufficiency is not
associated with cognitive impairment in multiple
sclerosis
Ralph HB Benedict 1,3 " Bianca Weinstock-Guttmam 1 , Karen Marr 2 , Vesela Valnarov 2 , Cheryl Kennedy 2 , Ellen Carl 2 ,
Christina Brooks 2 , David Hojnacki 1 and Robert Zivadinov 1,2
Abstract
Background: Chronic cerebrospinal venous insufficiency (CCSVI) has been reported in multiple sclerosis (MS) yet its
significance in relation to cognitive function is undetermined.
This study measured the association between the presence and severity of CCSVI and cognitive impairment in
patients with MS.
Methods: CCSVI was assessed using extra-cranial and trans-cranial Doppler sonography in 109 MS patients (79 with
relapsing-remitting, 23 with secondary-progressive and 7 with primary-progressive disease subtype). A subject was
considered CCSVI-positive if >2 venous hemodynamic criteria were fulfilled. The Minimal Assessment of Cognitive
Function in MS (MACFIMS) battery was administered assessing the full spectrum of cognitive domains known to be
affected by MS. Depression was quantified using the Beck Depression Inventory Fast Screen (BDIFS). Partial
correlations, analysis of variance (or covariance) and linear regression were used to examine the hypothesis that
CCSVI status is related to cognition or depression after controlling for education and gender.
Results: There were 64 (58.7%) patients who were considered CCSVI-positive. The regression models predicting
venous hemodynamic insufficiency severity score were not statistically significant for any of the MACFIMS predictor
variables. The analysis of variance tests showed a significant effect of CCSVI-positive diagnosis on cognitive ability in
only one of the 10 MACFIMS outcomes, and that one was in the opposite direction of the tested hypothesis. There
was no correspondence between CCSVI diagnosis and depression, as measured by the BDIFS.
Conclusions: We find no evidence of an association between the presence and severity of CCSVI with cognitive
impairment and depression in patients with MS.
Keywords: Multiple sclerosis, CCSVI, Cognition
Background
Multiple sclerosis (MS) is an inflammatory disease of the
central nervous system, causing both demyelination and
neurodegeneration [1,2]. As would be expected, a sub-
stantial number, roughly 50% [3-5], of MS patients have
cognitive impairment. In recently diagnosed or benign
course patients, the incidence ranges from 20% to 40%
[5,6] whereas in samples with a substantial secondary
* Correspondence: benedict@buffalo.edu
department of Neurology, State University of New York at Buffalo, 100 High
St, Buffalo, NY 14203, USA
department of Neurology, School of Medicine and Biomedical Sciences, 100
High St, Buffalo, NY 14203, USA
Full list of author information is available at the end of the article
progressive course, roughly 60% of patients are affected
[4]. The correlation between cognitive impairment and
brain atrophy is robust [7-9]. However, why some patients
show cognitive impairment and brain atrophy while others
do not is poorly understood.
Chronic cerebrospinal venous insufficiency (CCSVI) was
first reported in MS patients in 2009 [10]. As a vascular
condition, CCSVI is characterized by anomalies of the
main extra-cranial cerebrospinal venous routes, mainly in
internal jugular and azygos veins that are hypothesized to
interfere with normal venous outflow from the brain to
the periphery. Since then, the topic has met with unprece-
dented controversy following a wide range of reported
© 2013 Benedict et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
BiolVlGCl C6ntTcll Commons Attribution License (http://creativecommons.Org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Benedict et al. BMC Medicine 201 3, 1 1 :1 67
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Page 2 of 6
CCSVI frequencies in MS studies [11-13]. Diagnosis of
CCSVI implies a pathological condition the determination
of which is based mainly on color Doppler sonography
(DS) of extra- (neck) and intra-cranial veins using five ven-
ous hemodynamic (VH) criteria (with cutoff of >2 positive
criteria used for a diagnosis of CCSVI) [10,14]. So far,
published studies comparing the prevalence of CCSVI in
MS patients and controls [12,15] have not reproduced
the original findings of Zamboni et al. showing 100%
sensitivity/specificity [10,14]. While some groups did
report a higher prevalence in MS patients than controls
[16,17], others reported the opposite, that is, no greater
frequency in MS than in healthy persons [16,18-22]. In the
largest cohort studied to date, we found a CCSVI frequency
of 56.1% in MS patients compared to 22.7% in healthy
controls [23]; however, the condition was also detected at a
high frequency in patients with other neurologic diseases.
While not causative, some studies suggest that CCSVI
may be a risk factor for clinical worsening in MS [24-26],
although here, too, there are contradictory results [16,20].
In a large cohort study exploring the association between
CCSVI status and both lesion burden and brain atrophy in
MS, no relationship was found [27] .
If CCSVI is a risk factor for neurodegeneration or
progressive neurologic disability, we would expect signifi-
cant correlation between CCSVI and cognitive impairment
within MS cohorts. The present study was intended to
examine this hypothesis.
Methods
Participants
The neuropsychological data were collected in a single-
center, cross-sectional rater-blinded study that included
patients with definite MS who were undergoing deter-
mination of CCSVI status. Exclusion criteria were as
follows: (a) presence of relapse or steroid treatment
in the 30 days preceding study entry; (b) pre-existing
medical conditions known to be associated with brain
pathology; (c) pre-existing neuropsychiatric conditions
known to be associated with cognitive impairment, in-
cluding, for example, learning disability, major depres-
sive disorder, schizophrenia and traumatic brain injury,
among others; (d) history of cerebral congenital vascu-
lar malformations; (e) current alcohol or drug abuse;
and (f) pregnancy. Participants underwent a clinical
and neuropsychological examination, as well as both
trans- and extra-cranial DS. Demographic and clinical
information on all participating subjects was acquired
using a structured questionnaire and by examination.
The collected data included age, sex, age at disease
onset, age at diagnosis, symptoms at disease onset and
diagnosis, disease duration, Expanded Disability Status
Scale (EDSS) [28], disease subtype [29] and the results
of physical examination.
The study was approved by the Institutional Review
Board and informed consent was obtained from all patients.
Neuropsychological assessment
The neuropsychological examination was performed by
trained personnel who were blinded to the subjects'
clinical and CCSVI characteristics. While patients with
current major depressive episode were excluded from
the study, remitted or minor depression was permitted,
and the degree was quantified using the Beck Depression
Inventory Fast Screen (BDIFS) [30] which has been val-
idated in MS [31].
Next, the Minimal Assessment of Cognitive Function
in MS (MACFIMS) battery was administered [32], assessing
the full spectrum of cognitive domains known to be
affected by MS. The MACFIMS has been tested using
large prospective MS samples [4,33] and its psychometric
properties have been established through the development
of the individual tests and further research on the overall
battery [34]. Also, the tests on the MACFIMS correlate well
with brain magnetic resonance imaging (MRI) metrics in
MS samples [35,36]. The specific tests included are as
follows: the oral response - version of the Symbol Digit
Modalities Test (SDMT) [37], the Paced Auditory Serial
Addition Test (PASAT) [38], the California Verbal Learning
Test, 2nd edition (CVLT2) [39], the Brief Visual Memory
Test, Revised (BVMTR) [40], the Controlled Oral Word
Association Test (COWAT) [41], the Judgment of Line
Orientation Test (JLO) [42] and the Delis-Kaplan Executive
Function System (DKEFS) Sorting Test [43]. The tests
were normalized on the basis of recently published
normative data that account for demographics, such as
age and education [33].
Doppler sonography
Extra-and trans-cranial DS was performed on a color-coded
DS scanner (MyLab 25; Esaote-Biosound, Irvine, CA, USA)
equipped with a 5.0- to 10-Mhz transducer to examine
venous return in the internal jugular veins (IJVs) and
venous veins (Ws). The DS examination was performed by
two trained technologists who were blinded to the subjects'
demographic, clinical and neuropsychological character-
istics. The detailed scanning protocol and validation
were previously reported [23]. Briefly, the following five
VH parameters indicative of CCSVI were investigated:
1) reflux/bidirectional flow in the IJV and/or in the VV
in sitting and in supine positions, defined as flow di-
rected towards the brain for a duration of >0.88 second;
2) reflux/bidirectional flow in the deep cerebral veins
defined as reverse flow for a duration of 0.5 second in one
of the intra-cranial veins; 3) B-mode abnormalities or sten-
oses in IJVs, defined as a cross -sectional area (CSA) of this
vein <0.3 cm 2 ; 4) flow that is not Doppler-detectable in IJVs
and/or Ws despite multiple deep breaths; and 5) reverted
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postural control of the main cerebral venous outflow
pathway by measuring the difference of the CSA of the
IJVs in the supine and upright positions. A subject was
considered CCSVI-positive if >2 VH criteria were fulfilled,
as previously proposed [10].
We calculated the VH insufficiency severity score
(VHISS) [14,44], defined as a weighted sum of the
scores contributed by each individual VH criterion. The
formula for the VHISS calculations is: VHISS = VHISS1 +
VHISS2 + VHISS3 + VHISS4 + VHISS5. The VHISS score
is an ordinal measure of the overall extent and number of
VH flow pattern anomalies, with a higher value of VHISS
indicating a greater severity of abnormal flow. The mini-
mum possible VHISS value is 0 and the maximum 16.
Statistical analyses
Statistical analyses were performed using SPSS software.
As noted above, for descriptive purposes, the raw test
scores derived from neuropsychological examination were
normalized using previously published data [33]. Partial
correlations were performed using the Pearson product-
moment correlation coefficient, and the CCSVI positive
and negative groups were compared using analysis of
variance (or covariance) and chi-square tests. Linear
regression was used to examine the hypothesis that
CCSVI status as measured by the VHISS score is related
to cognitive function or depression, after controlling for
education and gender. Throughout, we employed a conser-
vative threshold of P <0.01 to control for type 1 error.
Results
Of the 109 patients enrolled, 79 were diagnosed with
relapsing-remitting, 23 with secondary-progressive, and
7 with primary-progressive disease subtype. All were
Caucasian, except two African- Americans and two of
Latin American heritage. The other descriptive statistics
including demographic, clinical, depression and cognitive
outcomes are presented in Table 1. The CCSVI positive
and negative MS groups were well matched, and no age,
disease duration, EDSS or disease subtype differences were
found. While the pattern of cognitive impairment was the
same as described in previous studies (SDMT and BVMTR
most sensitive), overall we found less impairment in this
sample as compared to some previous studies using the
same test battery [7,45-47].
There were 64 (58.7%) patients considered CCSVI-
positive and 45 negative (Table 1). As shown in Figure 1,
the total criteria VHISS score ranged 0 to 8. The median
was represented by 26 patients achieving a score of 3.
There were modest trends toward linear correlation be-
tween education (r = 0.25) and gender (r = -0.15) and the
VHISS score. The chi-square test showed correspondence
Table 1 Demographic, clinical and neuropsychological characteristics in multiple sclerosis patients with positive and
negative diagnosis of chronic cerebrospinal venous insufficiency (CCSVI)
All patients CCSVI positive CCSVI negative
number = 64 number = 45
Median
Mean
SD
Range
Mean z
Mean
SD
Mean
SD
Age
48
47.3
9.8
25
-66
46.8
9.0
47.6
10.4
Education
16
16.0
2.3
12
- 20
15.8
2.3
16.1
2.3
Male/female
38/72
27/38
11/34
Disease duration in years
9
10.5
8.2
01
-41
10.6
8.5
10.5
8.1
Disease course: RR/SP/PP
79/23/07
48/13/03
31/10/04
EDSS
2.5
3.3
1.9
0-
7.5
3.2
1.9
3.5
2.0
Beck Depression Inventory Fast Screen
1
2.4
2.6
0-
16
2.5
2.8
2.4
2.4
Symbol Digit Modalities Test
53
53.5
11.7
9-
74
-0.62
54.9
12.0
51.5
11.3
Paced Auditory Serial Addition Test
48
44.3
13.8
0-
60
-0.41
45.5
12.6
42.7
15.6
CVLT2Total Learning
55
54.0
11.1
23
-87
0.37
55.3
12.4
52.1
8.6
CVLT2Delayed Recall
12
11.5
3.2
2 -
16
0.17
11.7
3.5
11.1
2.7
BVMTR Total Learning
23
22.1
6.7
4-
34
-0.32
22.9
6.8
20.9
6.6
BVMTR Delayed Recall
9
8.6
2.4
1 -
12
-0.63
9.0
2.3
7.9
2.5
Controlled Oral Word Association Test
37
39.1
10.9
14
- 64
0.26
39.6
11.1
38.0
10.7
Judgment of Line Orientation Test
26
24.9
3.9
12
- 30
-0.59
25.6
3.4
24.0
4.6
DKEFS Sorting Correct Sorts
11
10.7
2.2
3 -
15
-0.07
10.7
2.3
10.7
2.0
DKEFS Sorting Description Score
40
40.3
8.7
10
- 58
-0.04
40.4
9.2
40.1
7.9
BVMTR, Brief Visuospatial Memory Test, Revised, CVLT2, California Verbal Learning Test, 2nd edition, DKEFS, Delis-Kaplan Executive Function System, EDSS,
Expanded disability status scale, PP, Primary progressive, RR, Relapsing-remitting, SP, Secondary progressive, SD standard deviation.
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3 4 5 6
Number of VH Criteria Met
Figure 1 Frequency distribution of venous hemodynamic
insufficiency severity score (VHISS) in 109 multiple sclerosis
(MS) patients.
between gender and the CCSVI-positive diagnosis (P = 0.05).
Therefore, education and gender were controlled for in
hypothesis testing models. There was no correspondence
between CCSVI and depression as measured by the BDIFS.
The regression models predicting VHISS score after
controlling for education and gender were not statistically
significant for any of the MACFIMS predictor variables.
The largest partial r in the analysis was -0.13 between
CVLTR Delayed Recall and the VHISS score (Table 2).
The analysis of covariance (ANCOVA) tests showed
a significant effect of CCSVI-positive diagnosis on
cognitive ability in one of the 10 MACFIMS outcomes
(Table 1, Figure 2). For BVMTR Delayed Recall, CCSVI-
positive patients showed better performance than their
CCSVI-negative counterparts (P = 0.009). The direction of
the effect was thus counter to expectation in that positive
patients achieved a score of 9.1 compared to 7.8 for the
CCSVI negative group.
Table 2 Correlation coefficients between venous
hemodynamic insufficiency severity score (VHISS) and
depression and cognition scores in multiple sclerosis
patients (n = 109)
Zero order r
Partial r
Beck Depression Inventory Fast Screen
0.10
0.13
Symbol Digit Modalities Test
-0.03
-0.02
Paced Auditory Serial Addition Test
-0.04
-0.07
CVLT2Total Learning
-0.06
-0.04
CVLT2Delayed Recall
-0.13
-0.13
BVMTR Total Learning
0.06
0.04
BVMTR Delayed Recall
0.10
0.09
Controlled Oral Word Association Test
0.02
-0.03
Judgment of Line Orientation Test
0.13
0.00
DKEFS Sorting Correct Sorts
0.04
-0.05
DKEFS Sorting Description Score
0.08
-0.01
♦ CCSVI Positive
-♦-CCSVI Negative
-3.00
COWAT JLO CVLT2 BVMTR SDMT PASAT DKEFS
Figure 2 Cognitive profiles of chronic cerebrospinal venous
insufficiency (CCSVI) negative (n = 45) and positive (n = 64)
multiple sclerosis patients. Each value represents a z score based on
previously published normative data accounting for demographic
variables. There are no significant differences for any test.
BVMTR Brief Visuospatial Memory Test, Revised, CVLT2 California Verbal
Learning Test, 2nd edition, DKEFS Delis-Kaplan Executive Function System.
Discussion
To the best of our knowledge, this is the first investigation
of neuropsychological status in MS patients in relation to
CCSVL In this sample of 109 MS patients, we find no
evidence of an association between CCSVI and cognitive
impairment. Moreover, no relationship between cognitive
performance and the severity of CCSVI criteria, as deter-
mined by DS, was detected in linear regression analysis.
When patients were categorized by their CCSVI status
(positive/negative), significant group differences emerged
for only one test, in a direction contrary to the hypothesis
that CCSVI is a risk factor for cognitive impairment in MS.
Similarly, there was no relationship between CCSVI and
depression in this cohort.
The CCSVI hypothesis has provoked great controversy
and debate in the MS research community since it was
first presented [11,13]. The hypothesis gained popularity
among MS patients because of the postulated possibility of
venous insufficiency correction using endovascular proce-
dures. While the diagnosis of CCSVI can be established
using noninvasive and invasive imaging techniques [12], the
validity of DS to establish the diagnosis of CCSVI remains
controversial. We showed previously that DS, in properly
trained hands, has high sensitivity and specificity for CCSVI
diagnosis, when compared to invasive imaging methods
[48,49]. This was the same method as used in this study,
and thus we are confident in the validity of the CCSVI
categorization in our analysis.
The true prevalence of CCSVI in MS patients is un-
known, and there is good evidence that the condition is
also found in patients with other neurologic diseases
[23]. In this study, 64% of the participating MS subjects
presented with CCSVI, which is similar to our previous
study [23]. The difference between the prevalence rates
of CCSVI-positive versus -negative MS patients in this
study is modest, and of uncertain meaning with respect
to MS pathology. Indeed, emerging studies point against
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CCSVI having a primary causative role in the development
of MS [11,13]. A multimodal approach will likely be needed
to determine the extent to which CCSVI is present in vari-
ous healthy and disease groups and MS subtypes [15].
Cognitive impairment is common in MS and can be reli-
ably quantified using neuropsychological tests emphasizing
episodic memory, mental processing speed and some
aspects of executive function [50]. Neuropsychological
deficits are also robustly correlated with brain MRI
measures, especially global and regional brain atrophy
[51]. The heterogeneity of neuropsychological presentation
among MS patients is influenced by many factors, including
genetics, gender, intelligence, disease course, comorbid
neuropsychiatric illness and health behaviors. The present
study employed consensus standard tests emphasizing mul-
tiple domains of cognitive function, allowing us to test, in a
comprehensive way, whether the presence and severity of
CCSVI can influence this important sphere of disability in
MS patients. No association between cognitive impairment
and the presence and severity of CCSVI was found. This is
consistent with our previous findings of a lack of associ-
ation between the presence of CCSVI and severity of lesion
burden and brain atrophy outcomes in MS patients [27].
There are a number of potential limitations in this
study. Selection of participants was based on the inclusion
or exclusion criteria in patients agreeing to undergo cogni-
tive testing. However, it may be that the most severe
patients presenting in our Center were not included in the
study. Another potential limit is not including a control
group. However, the aim of this study was not to assess
CCSVI prevalence, but rather an association with cognitive
impairment. Finally, the diagnosis of CCSVI was not con-
firmed by the use of other invasive diagnostic methods.
Conclusions
In conclusion, we find no evidence of an association
between the presence and severity of CCSVI and cognitive
impairment and depression in patients with MS.
Abbreviations
CCSVI: Chronic cerebrospinal venous insufficiency; DS: Doppler sonography;
IJV: Internal jugular vein.
Competing interests
RHBB receives royalties from Psychological Assessment Resources that are in
part associated with the Brief Visuospatial Memory Test Revised. RHBB has
acted as a consultant or scientific advisory board member for Bayer, Biogen
Idee, Actelion, and Novartis. He has received financial support for research
activities from Shire Pharmaceuticals, Accorda and Biogen Idee. BW-G has
participated in speaker's bureaus and served as a consultant for Biogen Idee,
Teva Neurosciences, EMD Serono, Pfizer, Novartis, Genzyme, and Acorda. She
also has received grant/research support from the agencies listed above as
well as ITN, Questcor and Shire. No other industry financial relationships
exist. DH has received speaker honoraria and consultant fees from Biogen
Idee, Teva Pharmaceutical Industries Ltd., EMD Serono, Pfizer Inc, and
Genzyme. RZ has received financial support for research activities from
Biogen Idee, Teva Pharmaceutical and Teva Neuroscience, EMD Serono,
Genzyme-Sanofi, Novartis, Greatbatch, Bracco and Questcor. He also received
personal compensation from Teva Pharmaceutical, Biogen Idee, Novartis,
Genzyme-Sanofi, EMD Serono, Bayer, Novartis and General Electric for
speaking and consultant services. KM, W, CK, EC and CB declare that they
have no competing interests.
Authors' contributions
All authors participated in discussion and correspondence to develop this
consensus opinion on the topics covered in this article. RHBB and RZ are the
lead authors because they lead the project and wrote the first draft of the
manuscript. All authors read and approved the final manuscript.
Study disclosure
The data used for this study were collected prospectively (between May
2010 and January 201 1), as part of a self-referred, fee-for-service program in
MS patients. Participants underwent clinical and imaging tests and were
evaluated for the presence of CCSVI. All patients provided signed informed
consent for entry of their test results in a central research database. The
database registry included MRI of the brain and neck, Doppler examination
of the brain and neck, neurological examination, neuropsychological testing
and blood draw for genetic testing. The current study on cognition and
CCSVI was funded by internal resources of the Buffalo Neuroimaging
Analysis Center and Baird MS Center, the Jacobs Neurological Institute,
University of Buffalo, as well as from the Direct MS Foundation and the
Jacquemin Family Foundation.
Author details
department of Neurology, State University of New York at Buffalo, 100 High
St, Buffalo, NY 14203, USA. 2 Buffalo Neuroimaging Analysis Center,
Department of Neurology, State University of New York at Buffalo, 100 High
St, Buffalo, NY 14203, USA. department of Neurology, School of Medicine
and Biomedical Sciences, 100 High St, Buffalo, NY 14203, USA.
Received: 27 February 2013 Accepted: 17 June 2013
Published: 18 July 2013
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Cite this article as: Benedict et al:. Chronic cerebrospinal venous
insufficiency is not associated with cognitive impairment in multiple
sclerosis. BMC Medicine 2013 1 1:167.